Process for preparing intermediates for pharmaceutically useful bicyclic compounds

ABSTRACT

Processes for preparing bicyclic compounds useful as anti-allergic, anti-inflammatory and/or cytoprotective agents are described, together with a process for preparing intermediates thereof.

FIELD OF THE INVENTION

The present invention relates to processes for preparing bicycliccompounds and intermediates thereof. Such compounds are useful asanti-allergic, anti-inflammatory and/or cytoprotective agents.

BACKGROUND OF THE INVENTION

Processes for making certain bicyclic compounds and intermediates havebeen described in various publications, such as in U.S. Pat. Nos.4,684,727; 4,628,055; 4,680,298; 4,492,702; 4,452,800; in JapanesePatent Disclosure No. 11,649; in European Patent Application No.0127135; and in the article "Phosphorous Pentoxide in Organic Synthesis,III - A New Synthesis of Pyrido [2,3-d]-pyrimidin-4(3H)-ones, O.Andersen and E. Pederson Liebigs Ann. Chem. 1982, 1012-1015. It would bedesirable to provide processes for preparing bicyclic compounds andtheir intermediates whose yields are as good as or better than methodspreviously taught. It would also be desirable to provide a process forpreparing said bicyclic compounds and intermediates which requires evenfewer steps than methods previously taught.

SUMMARY OF THE INVENTION

In one embodiment, the present invention is directed toward a processfor preparing a bicyclic compound of a formula ##STR1##

wherein W¹ and W² independently represent -CH=or --N═;

R², R³, R⁴ and R⁵ independently represent H, alkyl having from 1 to 12carbon atoms, alkenyl having from 3 to 8 carbon atoms, alkynyl havingfrom 3 to 8 carbon atoms, alkoxyalkyl having from 1 to 6 carbon atoms inthe alkoxy portion and from 2 to 6 atoms in the alkyl portion thereof,hydroxyalkyl having from 2 to 8 carbon atoms, cycloalkyl having from 3to 8 carbon atoms, acyloxyalkyl having from 1 to 6 carbon atoms in theacyloxy portion and from 2 to 8 carbon atoms in the alkyl portionthereof, and --R⁶ --CO₂ R⁰ wherein R⁶ represents an alkylene grouphaving from 1 to 6 carbon atoms and R⁰ represents hydrogen or an alkylgroup having from 1 to 6 carbon atoms, with the provisos that the OH ofthe hydroxyalkyl group and the acyloxy of the acyloxyalkyl group are notjoined to the same carbon atom as another heteroatom and that, when R²and/or R³ are alkenyl or alkynyl, there is at least one carbon-carbonsingle bond between the nitrogen atom and the carbon-carbon double ortriple bond and also with the proviso that R³ does not representhydrogen;

in addition, one of R² or R³ can be an aryl group or an aromaticheterocyclic group, either of which can be substituted with one to threesubstituents Y as defined below;

in further addition, R² and R³ can be joined together to represent aring which can contain from 2 to 8 carbon atoms, said ring optionallycontaining a --O--, --S-- and/or --NR⁴ -- heteroatomic group (wherein R⁴is as defined above) and/or optionally containing a carbon-carbon doublebond, and said ring optionally being substituted with one to threeadditional substituents R⁷ which substituents may be the same ordifferent and are each independently selected from OH with the provisothat OH is not on a carbon already joined to a hetero atom, --O--acylhaving from 1 to 6 carbon atoms, hydroxyalkyl having from 1 to 8 carbonatoms, alkoxyalkyl having from 1 to 6 carbon atoms in each alkyl portionthereof, alkyl having from 1 to 6 carbon atoms, alkenyl having from 3 to8 carbon atoms, alkynyl having from 3 to 8 carbon atoms, --COOR¹⁰wherein R¹⁰ is H, alkyl or aryl, or any two R⁷ substituent groups mayrepresent a hydrocarbon ring having from 4 to 8 total carbon atoms;

in still further addition, both R² and R³ can be joined together torepresent a polycyclic ring, which polycyclic ring can optionally besubstituted by one to three substituents groups R⁷ as defined above;

m is an integer of from 0 to 3;

n is an integer of from 0 to 2;

Q represents an aryl or an aromatic heterocyclic group which canoptionally be substituted with 1 to 3 substituents Y as defined below;

each Y substituent is independently selected from the group consistingof hydroxy, alkyl having from 1 to 6 carbon atoms, halogen, NO₂, alkoxyhaving from 1 to 6 carbon atoms, trifluoromethyl, cyano, cycloalkylhaving from 3 to 7 carbon atoms, alkenyloxy having from 3 to 6 carbonatoms, alkynyloxy having from 3 to 6 carbon atoms, hydroxyalkyl havingfrom 1 to 6 carbon atoms, --S(O)_(n) --R⁸ (wherein R⁸ represents alkylhaving from 1 to 6 carbon atoms and n is as defined above), --SO₂ NH₂,--CO--R⁹ (wherein R⁹ represents OH, --NH--R⁸ or --O--R⁸, where R⁸ is asdefined above), --O--B--COR⁹ (wherein B represents an alkylene grouphaving from 1 to 4 carbon atoms and R⁹ is as defined above), --NH₂,--NHCHO, --NH--CO--R⁹ (wherein R⁹ is as defined above, with the provisothat it is not hydroxy), --NH--COCF₃, --NH--SO₂ R⁸ (wherein R⁸ is asdefined above), and --NHSO₂ CF₃. The process (i.e. Process A) comprisesthe step of contacting an amino acetamide compound of the formula##STR2## wherein Y, W¹, W², R², R³, R⁴, R⁵, Q, m and n are as definedhereinbefore, and

R is any of the values for R⁴ or R⁵ with the proviso that R is nothydrogen,

with a base effective to selectively remove a proton from the methylenegroup (i.e. --CH₂ --) of said amino acetamide compound (V) in order tointramolecularly cyclize said compound to the bicyclic compound offormula (VII).

In preferred embodiments, as to the amino acetamide compound of formula(V) preferably Y is hydrogen, W¹ is preferably nitrogen and W² ispreferably CH, R is alkyl, more preferably methyl and m is 0, and R² andR³ are joined together to represent a ring containing four carbon atoms,and Q is phenyl. Preferably the base is potassium t-butoxide. As to thebicyclic compound of formula (VII), preferably Y is hydrogen, W¹ isnitrogen, W² is CH, m is zero, Q is phenyl, and R² and R³ are joinedtogether to represent a ring containing four carbon atoms. The processhas the advantages of being able to prepare the compound of formula(VII) in high yield, good purity, with low by-product formation usingrelatively mild reaction conditions. The process also has the advantageof providing a reaction medium which allows a simplified means forrecovery of the desired product.

Another embodiment of the present invention is directed to a secondprocess (i.e. Process B) for also preparing bicyclic compounds offormula (VII). The process comprises the steps of contacting a secondarysubstituted amine of the formula ##STR3## wherein Y, W¹, W², R⁴, R⁵, Q,m and n are as defined hereinbefore;

with an amino-substituted acetic acid derivative of the formula:##STR4## wherein

R² and R³ are as defined hereinbefore;

and R¹ represents the same values as for R;

with a base effective to cyclize said secondary substituted amine (IV)with said amino-substituted acetic acid derivative (VI) to give thedesired bicyclic compound (VII).

As to the substituted secondary amine compound (IV) preferably Y ishydrogen, W¹ is nitrogen, W² is CH, R is methyl , Q is phenyl and m iszero. As to the amino-substituted acetic acid derivative, preferably R¹is alkyl, preferably ethyl, R² and R³ are joined together to represent aring of four carbon atoms.

Also preferred is that the base is sodium hydride or potassiumt-butoxide.

The present invention (i.e. Process B) has the advantages of being ableto prepare the bicylic compound (VII) in high yields and good puritywith low-byproduct formation. Another advantage of the present inventionis that it provides a process whose reaction mixture allows a simplifiedmeans of recovery of the desired bicyclic compound (VII).

In yet another embodiment, the present invention is directed toward aprocess (i.e. Process C) for preparing a substituted acetamide compoundof the formula ##STR5## wherein Y, W¹, W², R, R⁴, R⁵, Q, m and n are asdefined hereinbefore; and X is halogen. The process comprises the stepof contacting a secondary amine compound of the formula ##STR6## whereinY, W¹, W², R, R⁴, R⁵, Q, m and n are as defined hereinbefore;

with a substituted acetic acid derivative of the formula ##STR7##wherein

X is as defined hereinbefore; and

R⁷ is a leaving group which is halogen, tosylate, mesylate or --OCOCH₂X¹

wherein X¹ is hydrogen or halogen; and said contacting is performed inthe presence of a proton accepting compound.

when R⁷ is OCOCH₂ X¹, derivative II is an anhydride. The substitutedacetamide compound (III) is useful as an intermediate in preparing thebicyclic compound (VII).

With regard to the secondary amine compound (I), preferably Y ishydrogen, W¹ is nitrogen, W² is CH, R is alkyl, more preferably methyl,m is zero, and Q is phenyl.

With regard to the substituted acetic acid derivative of formula (II),preferably X is halogen and R⁷ is halogen, more preferably chloro. Wherethe leaving group is an anhydride preferably X¹ is halogen, morepreferably chloro. Preferably the proton accepting compound is anepoxide, most preferably propylene oxide. The process of the presentinvention (i.e. Process C) has the advantage of providing a processuseful for preparing a substituted acetamide compound (III) useful forsubsequently preparing the bicyclic compound (VII). The present processalso has the advantage of preparing substituted acetamide compounds(III) in high yields, good purity, with low by-product formation usingrelatively mild reaction conditions.

DETAILED DESCRIPTION OF THE INVENTION

The processes of the present can be schematically illustrated asfollows: ##STR8##

It is understood and intended that the bicyclic compounds (VII) preparedby the processes of the present invention can exist in a zwitterionicform, such as illustrated below. ##STR9##

When utilized herein the terms listed hereinbelow, unless otherwiseindicated, are defined as follows:

halogen or halo - fluoro, chloro, bromo and iodo;

alkyl and alkoxy - comprise straight and branched carbon chains and,unless otherwise specified, contain from 1 to 6 carbon atoms;

alkenyloxy - comprise straight and branched carbon chains and, unlessotherwise specified, contain from 3 to 8 carbon atoms and comprising acarbon to carbon double bond;

alkynyloxy - comprise straight and branched carbon chains and, unlessotherwise specified, contain from 3 to 8 carbon atoms and comprising acarbon to carbon triple bond;

aryl - a carbocyclic group containing at least one benzene ring, withthe aryl groups preferably containing from 6 to 15 carbon atoms, morepreferably being phenyl or Y-substituted phenyl, e.g., phenyl, naphthyl,indenyl, indanyl, 4-chlorophenyl, 4-fluorophenyl, etc.;

aromatic heterocyclic - cyclic groups having at least one O, S and/or Nheterogroup interrupting the ring structure and having a sufficientnumber of unsaturated carbon to carbon bonds, nitrogen to carbon bonds,etc., to provide aromatic character, with the aromatic heterocyclicgroups preferably containing from 4 to 14 carbon atoms, e.g., pyridyl,furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl,pyridazinyl, 1,2,4-triazinyl, benzofuranyl, indolyl, pyrazolyl,oxazolyl, etc. Many times such heterocyclic groups can be bonded viavarious positions on the ring and all such variations are contemplated,e.g. 2- or 3-furanyl, 2-, 3- or 4-pyridyl, etc.

The compounds of the invention are comprised of a --(CR⁴ R⁵)_(m)--substituent wherein each R⁴ group and each R⁵ group may varyindependently. Thus, for example, when m equals 2 the following patternsof substitution (wherein hydrogen and CH₃ are used to represent anysubstituent, R⁴ or R⁵) are contemplated: --C(CH₃)₂ CH(CH₂ --, --CH₂C(CH₃)₂ --, --CH₂ CH(CH₃)--, --CH(CH₃)CH₂ --, --(C(CH₃)H)₂ -- and thelike. In addition when m equals 3, substituents such as --C(CH₃)₂ CH(C₂H₅)--CH₂ --, --CH(CH₃)--CH₂ CH(C₂ H₅)--, and CH₂ --CH(i--C₃ H₇)CH(C₂H₅)--are also contemplated.

The R² and R³ groups on the amino nitrogen in the compounds of theinvention can be the same or different. In some instances as notedabove, two of such groups or three of such groups may together representa heterocyclic ring system with the nitrogen of the amino group beingpart of such ring, e.g., a monocyclic or bicyclic ring. Examples ofsuitable --NR² R³ groups include the protonated secondary amino groupssuch as --NH(CH₃), --NH(--CH₂ --CH=CH₂), --NH(phenyl), --NH(--CH₂--CH═CH₂), --NH(phenyl), --NH(4--pyridyl), etc.; tertiary amino groupssuch as --NH(CH₃)₂, --N(CH₂ CO₂ H)C(CH₂ OH)₃, etc.;

As noted above, the compounds of the invention may include one to threeY substituents on the bicyclic ring system. Also, the Q group mayinclude one or two Y substituents. In cases where there is more than onesuch Y substituent, they may be the same or different. Thus, compoundshaving combinations of different Y substituents are contemplated withinthe scope of the invention. Examples of suitable Y substituents includeOH, methyl, chloro, bromo, methoxy, cyclohexyl, allyloxy, 2-propynyloxy,hydroxyethyl, methylthio, methylsulfonyl, carboxy, acetoxy,N-methylaminocarbonyl, acetoxymethoxy, acetamido, methylsulfonamido andthe like.

Turning to the processes of the present invention, in process A thebicyclic compounds of formula (VII) are prepared by contacting an aminoacetamide compound of formula (V) with a base in amounts and underconditions effective to selectively remove a proton from the methylgroup of said amino acetamide compound (V) in order to intramolecularlycyclize said compound (V). The amino acetamide compound of formula (V)can be contacted with the base at temperatures ranging from about -100°C. to about 100° C., preferably from about -70° to about 40° C.,depending upon the base employed. The reactants can be contacted atambient pressures although pressures less than or greater than ambientcan be employed. The reactants can be stirred or not stirred during thecontacting, although stirring is preferred. The reactants are contactedfrom a time effective to complete the reaction to the desired extent,for a period ranging from about 5 minutes to about 24 hours or more. Thecontacting can be conducted neat although generally compatible solventscan be employed. Such solvents include but are not limited to thechlorinated hydrocarbons such as carbon tetrachloride (CCl₄), methylenechloride (CH₂ Cl₂), and dichloroethane; to aliphatics such as C-1 toC-20 alkanes, cyclic or acyclic; aromatics such as benzene, toluene,xylene, alkylbenzenes and the like; to ethers such as diethyl ether andtetrahydrofuran (THF) and tertiary butyl-methyl ether; and to solventssuch as dimethylformamide (DMF), dimethylsulfoxide (DMSO), or mixturesthereof.

The base employed in Process A is any substance which will remove aproton from the methylene (--CH₂ --) group of the moiety ##STR10## inorder to intramolecularly cyclize the amino acetamide compound offormula (V).

Bases which can be employed in process A are generally non-aqueous basessuch as organo-alkali metals such as primary, secondary and tertiarybutyl lithiums, such as lithium diisopropyl amide, lithiumhexamethyldisilazane, sodium hexamethyldisilazane and potassiumhexamethyldisilazane; potassium t-butoxide or sodium methoxide; bases ofalkali and alkaline earth metals including carbonates such as sodium,potassium and cesium carbonates; hydroxides such as sodium and potassiumhydroxides; hydrides such as sodium or potassium hydrides; preferablythe base is sodium hydride, sodium methoxide, most preferably potassiumt-butoxide. Other bases which may be suitably employed are disclosed in"Modern Synthetic Reactions" by H. House, W. A. Benjamin, Inc., MenloPark, Calif., 1972, 856 pages. The amino acetamide compounds of formula(V) can be contacted with the base in an amount effective to cyclizecompound (V). The amount of base is employed in ratios ranging fromabout 1,000 to 2:1 mole; preferably from about 20 to 2:1, mostpreferably from about 8 to 2:1 (moles of base:mole amino acetamide (V)).Where employed, the solvents can range from about 1% to about 500% byweight of the amino acetamide compound (V).

After the reaction is completed, the desired bicyclic compound offormula (VII) is recovered by conventional separatory and recoverymethods such as chromatography, distillation, crystallization and thelike.

In process B for preparing the bicyclic compound of formula (VII), asecondary substituted amine of formula (IV) is contacted with anamino-substituted acetic acid derivative of formula (VI) in amounts andunder conditions effective to yield the desired bicyclic compound offormula (VII). The bases and solvents employed in process B areessentially the same as those in process A, described hereinbefore. Thesecondary substituted amine of formula (IV) is contacted with theamino-substituted acetic acid derivative of formula (V) at temperaturesranging from about -40° to about 200° C., preferably from about 25° toabout 180° C. The contacting is performed at ambient pressures althoughpressures is greater or less than ambient can be employed. Thecontacting of the reactants can be carried out from about 5 minutes toabout 72 hours or more until the reaction is substantially completed,preferably from about 1 hour to about 48 hours. Also preferred is thatthe reactants are stirred during the contacting procedures. Theamino-substituted acetic acid derivatives of formula (VI) can becontacted with the secondary substituted amines of formula (IV) inratios ranging from about 100 to 1:1 mole; preferably from about 10 to1:1, most preferably from about 6 to 1:1 (moles amino-substituted aceticacid derivative (VI):mole secondary substituted amine (IV)).

The base is employed in amounts ranging from about 1,000 to 3:1 mole,preferably from about 330 to 3:1, most preferably from about 15 to 3:1,(moles base:mole secondary substituted amine (IV)).

The reactants can be contacted neat, although preferably a solvent isemployed. A solvent can be employed in amounts ranging from about 1 to5,000% by weight of the secondary substituted amine (IV), preferablyfrom about 2% to about 1,000% by weight, more preferably from about 2 to50 percent.

After the reaction is completed, the desired bicyclic compound offormula (VII) is recovered by conventional separatory and recoverymethods such as described hereinbefore.

In yet another embodiment of the present invention, i.e. process C, thesubstituted acetamide compound of formula (III) is prepared bycontacting a secondary amine compound of formula (I) with a substitutedacetic acid derivative of formula (II) in the presence of a protonacceptor in amounts and under conditions effective to give thesubstituted acetamide compound (III).

The substituted acetic acid derivative (II) is employed in amountsranging from about 100 to 1:1 mole, preferably from about 25 to 1:1,most preferably from about 5 to 1:1 mole (moles substituted acetic acidderivative (II): mole secondary amine compound of formula (I)).

The term "proton acceptor" is defined as a compound which accepts eithera proton from an acid, or free protons in the reaction mixture, butgenerally will not accept a proton from the methylene group of theformula ##STR11## wherein --CH₂ -- is the methylene group. The protonacceptor is neither the secondary amine compound of formula (I) nor thesubstituted acetic acid derivatives of formula (II). The proton acceptorshould be compatible with the reactants and can be a base such asammonia (NH₃) or an organic base including primary amines such asmethylamine, β-naphthylamine, aniline, n-butyl amine, sec-butylamine,tert-butylamine, p-toluidine, 2,3-dimethylbenzenamine,2-phenylethylamine, benzylamine, cyclohexylamine, ethylamine,ethylenediamine, o-toluidine, m-toluidine, p-toluidine, urea; asecondary amine or a compound containing at least one secondary aminesuch as dimethylamine, diphenyl amine, N-methylpropylamine,diethylamine, diisopropyl amine, N-methylaniline, piperazine,piperidine, pyrrolidine; a tertiary amine such as trimethylamine,dimethylaniline, N,N-dimethyl-n-propylamine, N-methylpiperidine,N,N-diethylbutylamine, triethylamine; heterocyclic nitrogen containingcompounds such as isoquinoline, morpholine, purine, pyridine, pyrazine,pyrimidine, quinoline or polyvinyl pyridine; or to inorganic bases suchas those of alkali or alkaline earth metals discussed hereinbefore. Theproton acceptor can also be an epoxide of the formula: ##STR12## whereinT¹, T², T³ and T⁴ independently represent hydrogen, alkyl, alkenyl,alkynyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, as defined hereinbefore,and phenyl, halophenyl, alkyl phenyl having 1 to 6 carbons in the alkylportion, alkoxyphenyl having 1 to 6 carbons in the alkoxy portion,benzyl, halo benzyl, alkyl benzyl having 1 to 6 carbons in the alkylportion, alkoxy benzyl having 1 to 6 carbon atoms in the alkoxy portion,halo alkyl and cycloalkalkyl having 1 to 6 carbon atoms in the alkylportion. Representative epoxides suitable as proton acceptors includebut are not limited to ethylene oxide, propylene oxide, ethyl glycidate,epichlorohydrin, styrene oxide or mixtures thereof; and also to polymerbound and/or supported epoxides. Preferably, the epoxide is propyleneoxide. Alternatively, the epoxide can be prepared in-situ in thereaction mixture. The proton acceptor can also include mixtures of thebase and epoxide whose ratios can range from about 0.0001 to 10,000parts by weight base to 1 part by weight epoxide.

The proton acceptor or accepting compound is used in amounts effectiveto effectively scavange the requisite protons. Such amounts can rangefrom amounts greater than equimolar to about equimolar amounts i.e.about 10,000 to 1:1 mole, preferably from about 100 to 1 mole:1, mostpreferably from about 20 to 1:1 mole (moles proton acceptor:molesecondary amine compound of formula (I)).

Process C can be conducted neat, although a solvent is preferred. Wherea solvent is employed the contacting is conducted in the presence of asolvent whose amounts can range from an amount sufficient to at leastpartially solubilize one or both of the reactants and/or the desiredproduct to an excess of either starting reactant. Generally the amountof solvent can range from about 1 to 5,000 percent or more by weight ofthe individual reactant, preferably from about 2 to 1,200 percent byweight. The contacting of the reactants is conducted for a timeeffective to substantially complete the reaction, preferably from about5 minutes to about 24 hours or more, preferably from about 15 minutes toabout 4 hours. Generally the reactants are stirred during thecontacting.

Optionally, the process can be conducted in the presence of a catalystsuch as N,N-dimethylaniline, 4-dimethylaminopyridine or phase-transfercatalysts. The term "phase transfer catalyst" is intended to mean amaterial which catalyzes a reaction by the transfer of one phase toanother. Phase transfer catalysts suitable for carrying out the processof the present invention include the quaternary ammonium and phosphoniumsalts, ethers and tertiary amines, such as tributyl amine, such as thosedescribed in U.S. Pat. No. 3,969,360.

Where a catalyst is employed, a catalytic amount is used ranging fromabout 0.0001 to about 0.5 parts by weight of reactant, preferably fromabout 0.001 to about 0.1 parts by weight.

The reactants are contacted in Process C at a temperature effective toyield the derived product, generally at temperatures ranging from about-40° C. to about 200° C., preferably from about 0° to about 80° C.,depending upon the boiling point of the epoxide, solvent or startingmaterials. The contacting is performed at ambient pressures, althoughpressures greater than or less than ambient can be employed.

The following examples illustrate the present invention in a manner ofwhich it can be practiced but, as such, should not be construed aslimitations upon the overrall scope of the same.

EXAMPLE 1 PREPARATION OF4-HYDROXY-1-PHENYL-3-(1-PYRROLIDINYL)-1,8-NAPHTHYRIDIN-2-(1H)-ONE##STR13##

To a suspension of 1.4 g (4.1 millimoles (mM) of 3-pyridinecarboxylicacid-2(((1-pyrrolidinyl)acetyl) phenylamino)methyl ester int-butylmethylether at 0°-5 °C., 1.03 g (9.2 mM) potassium-t-butoxide isadded. The reaction mixture is stirred for an additional 0.5 hour at0-5° C. and allowed to warm up to room temperature. Next 0.75 mL glacialacetic acid is added very slowly. The resultant solid is filtered,washed with t-butylmethylether, methylene chloride, acetone, water andacetone. The product is air dried to give 0.94 g (73% yield) of titlecompound, a white solid.

EXAMPLE 2 PREPARATION OF4-HYDROXY-1-PHENYL-3-(1-PYRROLIDINYL)-1,8-NAPHTHYRIDIN-2-(1H)-ONE##STR14##

To a solution of 1.5 g (6.5 mM) 2-anilinonicotinic acid, methylester, indry xylenes at room temperature is added 0.69 g (14.54 M) of sodiumhydride (NaH) (50 percent (%) oil emulsion) followed by addition of asmall amount of N,N-dimethylformamide (DMF). The reaction mixture isheated to a temperature ranging between 85-95 degrees Centigrade (°C.)and 1.05 milliliters (mL) (6.5 mM) of ethyl-1-pyrrolidineacetate inxylene is slowly added over a period of 10 minutes. The reaction mixtureis heated for 1 to 3 hours prior to the addition of aliquots of 0.32 gNaH followed by 1.05 mL of ethyl-1-pyrrolidineacetate as described above(total 3 aliquots). Following addition of the aliquots, the reactionmixture is cooled to 0° C., quenched with a slow addition of glacialacetic acid, and then water is added. The product is filtered and washedwith water, acetone, methylene chloride, and acetone. The solid thenobtained is dried in vacuo to give 1.20 g (60% yield) of title compound,a white solid.

EXAMPLE 3 PREPARATION OF 3-PYRIDINE CARBOXYLIC ACID,2-((CHLOROACETYL)PHENYLAMINO), METHYLESTER ##STR15##

To a stirred solution of 26.3 g 2anilinonicotinic acid methylester (11.5mM) in t-butylmethylether at 50° C. (oil bath) under nitrogenatmosphere, 20.2 mL chloroacetylchloride (25.39 mM) followed by 32.4 mLpropylene oxide (46 mM) is added. The reaction mixture is stirred at 50°C. for 2 additional hours, cooled to room temperature, diluted witht-butylmethyl ether and washed with water containing NaHCO₃. The layersare separated, the aqueous layer is extracted with t-butylmethylether,the combined organic layers are dried over anhydrous Na₂ SO₄ andconcentrated in vacuo to obtain a gummy solid which is recrystallizedfrom t-butylmethyl ether to give 30.5 g (87% yield) of title compound,an off-white solid.

IR (CHCl₃) 1700,1740 cm⁻¹,

NMR (CDCl₃ δ4.1 (chloromethyl).

EXAMPLE 4 PREPARATION OF1-(1,2-DIHYDRO-4-HYDROXY-1-PHENYL-2-OXO-1,8-NAPHTHYRINDIN-3-YL)-PYRROLIDINIUMHYDROXIDE, INNER SALT

Step A: To a stirred solution of 25.45 g (0.11M) ofmethyl-2-phenylamino-nicotinate in 160 mL of t-butyl methyl ether(tBuOMe) (dried over 3A° sieves) heated to 50° (under N₂) 19.5 mL(2.2×0.11M) of propylene oxide was added. The reaction mixture washeated at 50° C. for 1.5 hours and then 300 mL tBuOMe was added. Thissolution (cooled to room temperature) was washed with 200 mL H₂ Ocontaining 9.37 g (0.11M) of NaHCO₃ followed by 30 mL of saturatedaqueous NaC1 solution. At this stage the product that crystallized outwas dissolved in 100 mL CH₂ Cl₂ and this CH₂ Cl₂ was mixed with tBuOMesolution. The solution, as is, was used for the next reaction.

Step B: To the above solution at room temperature under N₂, 37.2 mL(4×0.11M) of pyrrolidine was added and this solution was gently refluxedovernight. 9.3 mL (0.11M) of pyrrolidine was added, and the reaction wasrefluxed for an additional two hours. This mixture was diluted with 600mL tBuOMe and washed with 300 mL H₂ O and the aqueous layers were backextracted with 200 mL tBuOMe. The combined organic (tBuOMe) layer waswashed with 150 mL saturated aqueous NaCl soln., dried over anhydrousNa₂ SO₄, and then concentrated in vacuum (oil pump vacuum) to 64.6 g ofa crude brown semisolid, which was the methyl ester of2-[[1-pyrrolidinyl acetyl]phenylamino]-3-pyridine carboxylic acid.

Step C: The solid from step B above was suspended in 600 mL of cold (0°C.) tBuOMe (dried over 3A° sieves) under N₂. To this cold stirredmixture, 27.5 g (2.2×0.11M) potassium t-butoxide was added, the reactionmixture was stirred for 1 hour, and then it was quenched with 15 mL(2.4×0.11M) of glacial acetic acid.

The stirred reaction mixture was allowed to attain room temperature andthen 350 mL H₂ O was added to it. The resultant solid was filtered,washed with tBuOMe, H₂ O, a small amount of CH₂ Cl₂, acetone, and thenair dried to obtain 27.09 g of the white product1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-pyrrolidiniumhydroxide, inner salt. The crude product was crystallized from 300 mLCH₃ OH+16 mL conc. H₂ SO₄ at 50° C.+3g carbon; filtered, diluted with575 mL H₂ O, cooled to 0° C. and filtered; and draft oven dried at 60°C. for about 18 hours to give 22.2 g (82%) of crystallized whiteproduct.

PREPARATION OF STARTING MATERIALS

The starting materials employed in processes A, B and C are known or canbe prepared from known procedures. See, for example, U.S. Pat. Nos.4,684,727; 4,452,800, 4,492,702 and 4,680,298 whose preparativeteachings are incorporated herein by reference.

The present example, illustrates one method of which starting materialsof the present invention may be prepared, but as such, should not beconstrued as limitations upon the overall scope of the same.

EXAMPLE 5 PREPARATION OF 3-PYRIDINE CARBOXYLIC ACID,2(((1-PYRROLIDINYL)ACETYL)PHENYLAMINO)METHYL ESTER ##STR16##

To a gently refluxing stirred solution of 1 gram (g) (3.3 (mM) of3-pyridinecarboxylic acid2((chloroacetyl)phenylamino)methyl ester int-butylmethyl ether, 1.1 milliter (mL) pyrrolidine (13.2 mM) is added.The reaction mixture is refluxed for 2.5 hours, diluted witht-butylmethyl ether, and washed with water. The water layer is extractedwith t-butylmethyl ether, and the combined organic phases are washedwith a saturated aqueous sodium chloride (NaCl) solution, dried overanhydrous sodium sulfate (Na₂ SO₄) and then concentrated in vacuo togive 1.1 g (93% yield) of title compound, a tan solid.

IR (CHCl₃) 1685, 1725 cm⁻ 1,

NMR (CDCl₂) δ3.25 (N-CO-CH₂ -N).

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modifications,and variations thereof will be appoint to those of ordinary skill in theart. All such alternatives, modifications and variations are intended tofall within the spirit and scope of the present invention.

What is claimed is:
 1. A process for preparing a substituted acetamidecompound of the formula ##STR17## wherein W¹ and W² independentlyrepresent --CH═ or --N═; R⁴ and R⁵ independently represent H, alkylhaving from 1 to 12 carbon atoms, alkenyl having from 3 to 8 carbonatoms, alkynyl having from 3 to 8 carbon atoms, alkoxyalkyl having from1 to 6 carbon atoms in the alkoxy portion and from 2 to 6 atoms in thealkyl portion thereof, hydroxyalkyl having from 2 to 8 carbon atoms,cycloalkyl having from 3 to 8 carbon atoms, acyloxyalkyl having from 1to 6 carbon atoms in the acyloxy portion and from 2 to 8 carbon atoms inthe alkyl portion thereof, and -R⁶ -CO₂ R⁰ wherein R⁶ represents analkylene group having from 1 to 6 carbon atoms and R⁰ representshydrogen or an alkyl group having from 1 to 6 carbon atoms, with theprovisos that the OH of the hydroxyalkyl group and the acyloxy of theacyloxyalkyl group are not joined to the same carbon atom as anotherheteroatom;R is any of the values for R⁴ or R⁵ with the proviso that Ris not hydrogen m is an integer of from 0 to 3; n is an integer of from0 to 2; Q represents an aryl or an aromatic heterocyclic group which canoptionally be substituted with 1 to 3 substituents Y as defined below;each Y substituent is independently selected from the group consistingof hydroxy, alkyl having from 1 to 6 carbon atoms, halogen, NO₂, alkoxyhaving from 1 to 6 carbon atoms, trifluoromethyl, cyano, cycloalkylhaving from 3 to 7 carbon atoms, alkenyloxy having from 3 to 6 carbonatoms, alkynyloxy having from 3 to 6 carbon atoms, hydroxyalkyl havingfrom 1 to 6 carbon atoms, --S(O)_(n) -R⁸ (wherein R⁸ represents alkylhaving from 1 to 6 carbon atoms and n is as defined above), --SO₂, NH₂,--CO-R⁹ (wherein R⁹ represents OH, --NH--R⁸, or --O-R⁸, where R⁸ is asdefined above), --O-B-COR⁹ (wherein B represents an alkylene grouphaving from 1 to 4 carbon atoms and R⁹ is as defined above), --NH₂,--NHCHO, --NH-CO-R⁹ (wherein R⁹ is as defined above, with the provisothat it is not hydroxy), --NH-COCF₃, -NH-SO₂ R⁸ (wherein R⁸ is asdefined above), and -NHSO₂ CF₃, comprising contacting a secondary aminecompound of the formula: ##STR18## wherein Y, W¹, W², R⁴, R⁵, m and nare as defined hereinbefore, with a substituted acetic acid derivativeof the formula X--CH₂ COR⁷ II)wherein X is halogen; and R⁷ is a leavinggroup which is halogen, tosylate, mesylate or OCOCH₂ X² wherein X¹ ishydrogen or halogen; and said contacting is performed in the presence ofan epoxide employed in amounts greater than equimolar to about equimolaramounts relative to the secondary amine compound of Formula (I).
 2. Theprocess of claim 1, wherein as to the secondary amine compound offormula I, Y is hydrogen, W¹ is nitrogen, W² is CH, R is methyl, m iszero and Q is phenyl.
 3. The process of claim 1, wherein as to thesubstituted acetic acid derivative of formula (II), X is halogen and R⁷is halogen.
 4. The process claim 1, wherein as to the substituted aceticacid derivative of formula (II), X is chloro and R⁷ is chloro.
 5. Theprocess of claim 1, wherein the substituted acetic acid derivative offormula (II) is an anhydride and X¹ is chloro.
 6. The process of claim1, wherein the epoxide is in admixture with a base.
 7. The process ofclaim 6 wherein the base is sodium bicarbonate.
 8. The method of claim 1wherein the epoxide is propylene oxide.